U.S. patent number 6,355,676 [Application Number 09/743,978] was granted by the patent office on 2002-03-12 for fumaric acid micro tablets.
This patent grant is currently assigned to Fumapharm AG. Invention is credited to Rajendra Kumar Joshi, Hans-Peter Strebel.
United States Patent |
6,355,676 |
Joshi , et al. |
March 12, 2002 |
**Please see images for:
( Certificate of Correction ) ** |
Fumaric acid micro tablets
Abstract
The present invention relates to the use of one or more salts of
fumaric acid monoalkyl esters of the general formula ##STR1##
optionally in admixture with dialkyl fumarate of the formula
##STR2## wherein A is a bivalent cation from the series consisting
of Ca, Mg, Zn or Fe or a monovalent cation from the series Li, Na
or K, respectively, and n denotes the numeral 1 or 2 depending on
the type of cation, and, optionally, commonly used pharmaceutical
excipients and vehicles for preparing a pharmaceutical composition
in the form of micro-tablets or micro-pellets for the treatment of
psoriatic arthritis, neurodermatitis, psoriasis and enteritis
regionalis Crohn.
Inventors: |
Joshi; Rajendra Kumar (Zurich,
CH), Strebel; Hans-Peter (Muri, CH) |
Assignee: |
Fumapharm AG (Muri,
CH)
|
Family
ID: |
7885018 |
Appl.
No.: |
09/743,978 |
Filed: |
January 17, 2001 |
PCT
Filed: |
October 08, 1999 |
PCT No.: |
PCT/EP99/07568 |
371
Date: |
January 17, 2001 |
102(e)
Date: |
January 17, 2001 |
PCT
Pub. No.: |
WO00/10681 |
PCT
Pub. Date: |
March 02, 2000 |
Foreign Application Priority Data
|
|
|
|
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Oct 20, 1998 [DE] |
|
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198 48 260 |
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Current U.S.
Class: |
514/494;
514/547 |
Current CPC
Class: |
A61P
37/00 (20180101); A61P 17/00 (20180101); A61K
9/4858 (20130101); A61K 31/22 (20130101); A61P
1/04 (20180101); A61P 17/06 (20180101); A61P
1/00 (20180101); A61P 19/02 (20180101); A61K
31/22 (20130101); A61K 2300/00 (20130101); A61K
9/2866 (20130101); A61K 9/2054 (20130101); A61K
9/2059 (20130101) |
Current International
Class: |
A61K
31/21 (20060101); A61K 31/22 (20060101); A61K
9/48 (20060101); A61K 9/20 (20060101); A61K
9/28 (20060101); A61K 031/315 () |
Field of
Search: |
;514/547,494 |
References Cited
[Referenced By]
U.S. Patent Documents
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|
|
4851439 |
July 1989 |
Speiser et al. |
4959389 |
September 1990 |
Speiser et al. |
5424332 |
June 1995 |
Speiser et al. |
5451667 |
September 1995 |
Speiser et al. |
|
Foreign Patent Documents
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|
2530372 |
|
Jan 1977 |
|
DE |
|
2621214 |
|
Nov 1977 |
|
DE |
|
3834794 |
|
Apr 1990 |
|
DE |
|
0312697 |
|
Apr 1989 |
|
EP |
|
Other References
Sebok, Bela et al., "Antiproliferative and Cytotoxic profiles of
Antipsoriatic Fumaric Acid Derivatives in Keratinocyte Cultures",
European Journal of Pharm., Environ., Toxicol.Pharmacol. Sect.,
1994, vol. 270, pp. 79-87. .
Nibbering, P.H. et al., "Intracellular Signalling by Binding Sites
for the Antipsoratic Agent Monomethylfumarate on Human
Granulocytes", British J. Dermatiol., 1997, vol. 137, pp. 65-75.
.
Altmeyer, P. et al., "Systemische Therapie der Psoriasis", T &
E Dermatologie Jg., 1997, vol. 27, pp. 380-382, 384--not
translated. .
Nibbering, Peter H., "Effects of Monomethylfumarate on Human
Granulocytes", Journal of Investigative Dermatology, 1993, vol.
101, pp. 37-42. .
Medline Abstract of Bayard et al., "Peroral long-term treatment of
psoriasis using fumaric acid derivatives", Hautarzt, 1987 May,
38(5), pp. 279-285..
|
Primary Examiner: Reamer; James H.
Attorney, Agent or Firm: Sieberth & Patty, L.L.C.
Parent Case Text
This application is a 371 continuation of PCT Application
PCT/EP99/07568, filed Oct. 8, 1999, the text of which is not in
English, which PCT Application claims priority on German
Application No. 198 48 260.4, filed Oct. 20, 1998, the text of
which is not in English.
Claims
What is claimed is:
1. A method of preparing a pharmaceutical composition for treatment
of psoriatic arthritis, neurodermatitis, psoriasis, or enteritis
regionalis Crohn, which method comprises forming micro-tablets or
micro-pellets from one or more salts of fumaric acid monoalkyl
esters of the general formula ##STR5##
optionally in admixture with dialkyl fumarate of the formula
##STR6##
wherein A is a bivalent cation from the series consisting of Ca,
Mg, Zn, or Fe, or a monovalent cation from the series Li, Na, or K,
respectively, and n denotes the numeral 1 or 2 depending on the
type of cation, and, optionally, at least one pharmaceutically
acceptable excipient or vehicle.
2. The method according to claim 1, characterized in that the
calcium salt of fumaric acid monoethyl ester or monomethyl ester is
the salt of fumaric acid monoalkyl ester used in forming said
composition.
3. The method according to claim 1, characterized in that the
calcium salt of the fumaric acid monoalkyl ester in admixture with
dimethyl fumarate is used in forming said composition.
4. The method according to claim 2, characterized in that the
calcium salt of fumaric acid monoethyl or monomethyl ester is used
in admixture with dimethyl fumarate in forming said
composition.
5. The method according to claim 1, characterized in that the
calcium and zinc salts of the fumaric acid monoalkyl ester in
admixture with dimethylfumarate are used in forming said
composition.
6. The method according to claim 1, characterized in that the
calcium, magnesium, and zinc salts of the fumaric acid monoethyl
ester in admixture with dimethylfumarate are used in forming said
composition.
7. The method according to claim 1, characterized in that the salt
of the fumaric acid monoalkyl ester used in forming said
composition is the calcium salt of the fumaric acid monoalkyl
ester, and the amount thereof per dosage form is 10 to 300 mg, the
total weight of the active ingredients per dosage form being 10 to
300 mg.
8. The method according to any of claims 2 to 6, characterized in
that said calcium salt is used in an amount per dosage form of 10
to 300 mg, the total weight of the active ingredients per dosage
form being 10 to 300 mg.
9. The method according to claim 3, characterized in that 10 to 290
parts by weight of the calcium salt of the fumaric acid monoalkyl
ester and 290 to 10 parts by weight of dimethyl fumarate are used
in forming said composition, the total weight of the active
ingredients per dosage form being 20 to 300 mg.
10. The method according to claim 9, characterized in that said
calcium salt is the calcium salt of fumaric acid monoethyl or
monomethyl ester.
11. The method according to claim 5, characterized in that 10 to
250 parts by weight of the calcium salt of the fumaric acid
monoalkyl ester, 1 to 50 parts by weight of dimethyl fumarate, and
1 to 50 parts by weight of the zinc salt of the fumaric acid
monoalkyl ester are used in forming said composition, the total
weight of the active ingredients per dosage form being 20 to 300
mg.
12. The method according to claim 1, characterized in that 10 to
250 parts by weight of the calcium salt of the fumaric acid
monoalkyl ester, 250 to 10 parts by weight of dimethyl fumarate, 1
to 50 parts by weight of the magnesium salt of the fumaric acid
monoalkyl ester and 1 to 50 parts by weight of the zinc salt of the
fumaric acid monoalkyl ester are used in forming said composition,
the total weight of the active ingredients per dosage form being 30
to 300 mg.
13. The method according to claim 12, characterized in that the
said calcium salt is the calcium salt of fumaric acid monoethyl
ester or the calcium salt of fumaric acid monomethyl ester.
14. The method according to claim 12, characterized in that said
calcium salt, said magnesium salt, and said zinc salt are,
respectively, the calcium, the magnesium, and the zinc salts of
fumaric acid monoethyl ester.
15. The method according to any of claims 1, 2, 3, 4, 5, 6, 7, 9,
10, 11, 12, 13, or 14 wherein the micro-tablets or micro-pellets
are provided with an enteric coating (coating resistant to gastric
acid).
16. The method according to any of claims 1, 2, 3, 4, 5, 6, 7, 9,
10, 11, 12, 13, or 14 wherein the micro-tablets or micro-pellets
are filled into capsules or sachets.
17. The method according to claim 8 wherein the micro-tablets or
micro-pellets are provided with an enteric coating (coating
resistant to gastric acid).
18. The method according to claim 8 wherein the micro-tablets or
micro-pellets are filled into capsules or sachets.
19. A pharmaceutical composition for treatment of psoriatic
arthritis, neurodermatitis, psoriasis, or enteritis regionalis
Crohn, which composition comprises micro-tablets or micro-pellets
comprising at least one salt of a fumaric acid monoalkyl ester of
the formula ##STR7##
optionally in admixture with dialkyl fumarate of the formula
##STR8##
wherein A is a bivalent cation from the series consisting of Ca,
Mg, Zn, or Fe, or a monovalent cation from the series Li, Na, or K,
respectively, and n denotes the numeral 1 or 2 depending on the
type of cation, and, optionally, at least one pharmaceutically
acceptable excipient or vehicle.
20. A composition according to claim 19 wherein said at least one
salt of a fumaric acid monoalkyl ester is the calcium salt of
fumaric acid monoethyl ester or of fumaric acid monomethyl
ester.
21. A composition according to claim 19 wherein said at least one
salt of a fumaric acid monoalkyl ester is the calcium salt of said
fumaric acid monoalkyl ester, and wherein dimethyl fumarate is in
admixture with said calcium salt in said composition.
22. A composition according to claim 20 wherein dimethylfumarate is
in admixture with the calcium salt of fumaric acid monoethyl ester
or fumaric acid monomethyl ester in said composition.
23. A composition according to claim 19 wherein said at least one
salt of a fumaric acid monoalkyl ester is a mixture of the calcium
and the zinc salts of said fumaric acid monoalkyl ester, and
wherein dimethylfumarate is in admixture with said calcium and zinc
salts in said composition.
24. A composition according to claim 19 wherein said at least one
salt of a fumaric acid monoalkyl ester is a mixture of the calcium,
the magnesium, and the zinc salts of fumaric acid monoethyl ester,
and wherein dimethylfumarate is in admixture with said calcium,
magnesium, and zinc salts in said composition.
25. A composition according to claim 19 wherein said at least one
salt of a fumaric acid monoalkyl ester is the calcium salt of said
fumaric acid monoalkyl ester, and wherein said composition contains
per dosage form 10 to 300 mg of said calcium salt, with the total
weight of the active ingredients being 10 to 300 mg per dosage
form.
26. A composition according to any of claims 20 to 24 wherein said
composition contains per dosage form 10 to 300 mg of said calcium
salt, with the total weight of the active ingredients being 10 to
300 mg per dosage form.
27. A composition according to claim 21 wherein said composition
contains said calcium salt and the dimethyl fumarate in proportions
of 10 to 290 parts by weight of said calcium salt and 290 to 10
parts by weight of dimethyl fumarate, with the total weight of the
active ingredients being 20 to 300 mg per dosage form.
28. A composition according to claim 27 wherein said calcium salt
is the calcium salt of fumaric acid monoethyl or monomethyl
ester.
29. A composition according to claim 23 wherein said composition
contains said calcium salt, said zinc salt, and the dimethyl
fumarate, in proportions of 10 to 250 parts by weight of said
calcium salt, 1 to 50 parts by weight of said zinc salt, and 1 to
50 parts by weight of dimethyl fumarate, with the total weight of
the active ingredients being 20 to 300 mg per dosage form.
30. A composition according to claim 19 wherein said composition
contains the calcium, magnesium, and zinc salts of said fumaric
acid monoalkyl ester, and the dimethyl fumarate in proportions of
10 to 250 parts by weight of said calcium salt, 1 to 50 parts by
weight of said magnesium salt, 1 to 50 parts by weight of said zinc
salt, and 250 to 10 parts by weight of the dimethyl fumarate, with
the total weight of the active ingredients being 30 to 300 mg per
dosage form.
31. A composition according to claim 30 wherein said calcium salt
is the calcium salt of fumaric acid monoethyl ester or the calcium
salt of fumaric acid monomethyl ester.
32. A composition according to claim 30 wherein said calcium salt,
said magnesium salt, and said zinc salt are, respectively, the
calcium, the magnesium, and the zinc salts of fumaric acid
monoethyl ester.
33. A composition according to any of claims 19, 20, 21, 22, 23,
24, 25, 27, 28, 29, 30, 31, or 32 wherein the micro-tablets or
micro-pellets are provided with an enteric coating.
34. A composition according to any of claims 19, 20, 21, 22, 23,
24, 25, 27, 28, 29, 30, 31, or 32 wherein the micro-tablets or
micro-pellets are filled into capsules or sachets.
35. A composition according to claim 26 wherein the micro-tablets
or micro-pellets are provided with an enteric coating.
36. A composition according to claim 26 wherein the micro-tablets
or micro-pellets are filled into capsules or sachets.
37. A method for treatment of psoriatic arthritis, neurodermatitis,
psoriasis, or enteritis regionalis Crohn, which method comprises
administering to the patient a pharmaceutical composition
comprising micro-tablets or micro-pellets which comprise at least
one salt of a fumaric acid monoalkyl ester of the formula
##STR9##
optionally in admixture with dialkyl fumarate of the formula
##STR10##
wherein A is a bivalent cation from the series consisting of Ca,
Mg, Zn, or Fe, or a monovalent cation from the series Li, Na, or K,
respectively, and n denotes the numeral 1 or 2 depending on the
type of cation, and, optionally, at least one pharmaceutically
acceptable excipient or vehicle.
38. A method according to claim 37 wherein said at least one salt
of a fumaric acid monoalkyl ester is the calcium salt of fumaric
acid monoethyl ester or of fumaric acid monomethyl ester.
39. A method according to claim 37 wherein said at least one salt
of a fumaric acid monoalkyl ester is the calcium salt of said
fumaric acid monoalkyl ester, and wherein dimethyl fumarate is in
admixture with said calcium salt in said composition.
40. A method according to claim 38 wherein dimethylfumarate is in
admixture with the calcium salt of fumaric acid monoethyl ester or
fumaric acid monomethyl ester in said composition.
41. A method according to claim 37 wherein said at least one salt
of a fumaric acid monoalkyl ester is a mixture of the calcium and
the zinc salts of said fumaric acid monoalkyl ester, and wherein
dimethylfumarate is in admixture with said calcium and zinc salts
in said composition.
42. A method according to claim 37 wherein said at least one salt
of a fumaric acid monoalkyl ester is a mixture of the calcium, the
magnesium, and the zinc salts of fumaric acid monoethyl ester, and
wherein dimethylfumarate is in admixture with said calcium,
magnesium, and zinc salts in said composition.
43. A method according to claim 37 wherein said at least one salt
of a fumaric acid monoalkyl ester is the calcium salt of said
fumaric acid monoalkyl ester, and wherein said composition contains
per dosage form 10 to 300 mg of said calcium salt, with the total
weight of the active ingredients being 10 to 300 mg per dosage
form.
44. A method according to any of claims 38 to 42 wherein said
composition contains per dosage form 10 to 300 mg of said calcium
salt, with the total weight of the active ingredients being 10 to
300 mg per dosage form.
45. A method according to claim 39 wherein said composition
contains said calcium salt and the dimethyl fumarate in proportions
of 10 to 290 parts by weight of said calcium salt and 290 to 10
parts by weight of dimethyl fumarate, with the total weight of the
active ingredients being 20 to 300 mg per dosage form.
46. A method according to claim 45 wherein said calcium salt is the
calcium salt of fumaric acid monoethyl or monomethyl ester.
47. A method according to claim 41 wherein said composition
contains said calcium salt, said zinc salt, and the dimethyl
fumarate, in proportions of 10 to 250 parts by weight of said
calcium salt, 1 to 50 parts by weight of said zinc salt, and 1 to
50 parts by weight of dimethyl fumarate, with the total weight of
the active ingredients being 20 to 300 mg per dosage form.
48. A method according to claim 37 wherein said composition
contains the calcium, magnesium, and zinc salts of said fumaric
acid monoalkyl ester, and the dimethyl fumarate in proportions of
10 to 250 parts by weight of said calcium salt, 1 to 50 parts by
weight of said magnesium salt, 1 to 50 parts by weight of said zinc
salt, and 250 to 10 parts by weight of the dimethyl fumarate, with
the total weight of the active ingredients being 30 to 300 mg per
dosage form.
49. A method according to claim 48 wherein said calcium salt is the
calcium salt of fumaric acid monoethyl ester or the calcium salt of
fumaric acid monomethyl ester.
50. A method according to claim 48 wherein said calcium salt, said
magnesium salt, and said zinc salt are, respectively, the calcium,
the magnesium, and the zinc salts of fumaric acid monoethyl
ester.
51. A method according to any of claims 37, 38, 39, 40, 41, 42, 43,
45, 46, 47, 48, 49, or 50 wherein the micro-tablets or
micro-pellets are provided with an enteric coating.
52. A method according to any of claims 37, 38, 39, 40, 41, 42, 43,
45, 46, 47, 48, 49, or 50 wherein the micro-tablets or
micro-pellets are filled into capsules or sachets.
53. A method according to claim 44 wherein the micro-tablets or
micro-pellets are provided with an enteric coating.
54. A method according to claim 44 wherein the micro-tablets or
micro-pellets are filled into capsules or sachets.
Description
The present invention relates to the use of certain fumaric acid
monoalkyl ester salts either alone or in combination with a dialkyl
fumarate for preparing micro-tablets for the treatment of psoriatic
arthritis, neurodermatitis, psoriasis and enteritis regionalis
Crohn.
EP-A-0 188 749 already describes fumaric acid derivatives and
pharmaceutical compositions containing the same for the treatment
of psoriasis. Likewise, pharmaceutical compositions for treating
psoriasis which contain a mixture of fumaric acid and other fumaric
acid derivatives are known from DE-A-25 30 372. A content of free
fumaric acid is obligatory.
DE-A-26 21 214 describes drugs for treating psoriasis which contain
fumaric acid monoethyl ester and mineral salts thereof as the
active ingredient. The use of fumaric acid monoethyl ester salts of
calcium, zinc and magnesium and of fumaric acid dimethyl ester for
the treatment of psoriasis is also known from the publication
"Hautarzt" (Dermatologist) 1987, pages 279 to 285.
Finally, EP-A-0 312 697 discloses pharmaceutical compositions
containing one or more compounds selected from the calcium,
magnesium, zinc and iron salts of fumaric acid monomethyl ester,
alone or preferably in admixture with C.sub.1-5 alkyl fumarates. A
preparation according to example 4 of this document contains 87.5
mg of monoethyl fumarate Ca salts, 120.0 mg of dimethyl fumarate,
5.0 mg of monoethyl fumarate Mg salt and 3.0 mg of monoethyl
fumarate Zn salt, which corresponds to 164 mg of fumaric acid. The
preparation is presented in the form of enteric-coated tablets and
is approved for distribution in the German market under the
trademark Fumaderm.RTM..
As early as phase 3 of the clinical tests and in post-marketing
studies of this product, it was found that about 60% of the
patients developed gastro-intestinal symptoms in the form of
diarrhoea, stomach pains and bloating during the initial phase of
the Fumaderm.RTM. therapy. Other side effects are so-called
flushes, i.e. redness of the face, and sensations of heat.
Even though the tablets are generally tolerated relatively well,
the above-mentioned symptoms keep occurring, especially at the
onset of therapy. In the course of the treatment, these undesirable
side effects often decrease. However, the intake of Fumaderm.RTM.
causes severe gastro-intestinal complaints in some patients. These
symptoms in the stomach and intestine affect patient compliance and
can be so unpleasant for the patient that therapy is sometimes
discontinued.
Therefore, it was the object of the present invention to provide a
pharmaceutical preparation which avoids the above-mentioned side
effects, especially gastro-intestinal complaints, while the same
pharmaceutical ingredients are administered.
Tests carried out by the Applicant have shown that methyl hydrogen
fumarate, a metabolite of dimethyl fumarate which forms the main
component of the preparation Fumaderm.RTM. initially increases the
endotoxin-stimulating TNF-.alpha. secretion in human mononuclear
cells of the peripheral blood (peripheral blood mononuclear cells
=PBMC) and in isolated monocytes. With multiple re-exposure, the
endotoxin-induced increase in TNF-.alpha. secretion is reduced,
i.e. adaptation takes place.
Possibly, this initial induction of TNF-.alpha. is responsible for
the known side effect of the Fumaderm.RTM. preparation such as
gastro-intestinal complaints or the flush symptoms. The tendency
towards decrease of endotoxin-induced TNF-.alpha. secretion after
repeated methyl hydrogen fumarate exposure may be an explanation
for the adaptation effect, i.e. the decrease of side effects after
sustained Fumaderm.RTM. therapy. Accordingly, it was the first
objective of additional tests to inhibit TNF-.alpha. secretion with
other drugs and thus to control the side effects of Fumaderm.RTM.
administration.
Surprisingly and unexpectedly, it was found in the course of these
tests that formulation of the active ingredient in the form of
micro-tablets resulted in a substantial reduction of
gastro-intestinal symptoms. Therefore, the object of the invention
is achieved by using one or more fumaric acid monoalkyl ester salts
of the general formula ##STR3##
optionally in admixture with dialkyl fumarate of the formula
##STR4##
wherein A is a bivalent cation from the series consisting of Ca,
Mg, Zn or Fe or a monovalent cation from the series Li, Na or K,
respectively, and n denotes the numeral 1 or 2 depending on the
type of cation, and, optionally, commonly used pharmaceutical
excipients and vehicles for preparing a pharmaceutical composition
in the form of micro-tablets or micro-pellets for the treatment of
psoriatic arthritis, neurodermatitis, psoriasis and enteritis
regionalis Crohn.
Preferably, the size or the mean diameter, respectively, of the
micro-pellets or micro-tablets is in the range of 300 to 2.000
.mu.m, especially in the range of 500 to 1.500 .mu.m and most
preferably 1.000 .mu.m.
The micro-tablets or micro-pellets may be filled in capsules or
sachets and administered in this form. In addition, the
micro-tablets themselves or the capsules may be provided with an
enteric coating which is applied by conventional processes.
Capsules may be hard or soft gelatine capsules.
Preferred compositions according to the invention contain the
calcium salt of the fumaric acid monomethyl ester and/or the
calcium salt of the fumaric acid monoethyl ester, optionally in
admixture with dimethyl fumarate. The total weight of the active
ingredients is 10 to 300 mg. Preferably, the composition in the
form of micro-tablets contains 10 to 290 parts by weight of the
fumaric acid monoalkyl ester (calcium salt) and 290 to 10 parts by
weight of dimethyl fumarate. According to another embodiment, this
composition may also contain 1 to 50 parts by weight of fumaric
acid monoalkyl ester zinc salt.
Another preferred embodiment in the form of micro-tablets contains
1 to 250 parts by weight of fumaric acid monoalkyl ester (calcium
salt), 250 to 10 parts by weight of dimethyl fumarate, 1 to 50
parts by weight of fumaric acid monoalkyl ester (magnesium salt)
and 1 to 50 parts by weight of fumaric acid monoalkyl ester (zinc
salt), the total weight of the active ingredients being 30 to 300
mg.
For systemic initiation as well as for termination of the treatment
in stages (decreasing dosage), a low dose is advantageous. Such a
dose may, for example, consist of 30 mg of dimethyl fumarate, 20 mg
of monoethyl fumarate (calcium salt) and 3 mg of monoethyl fumarate
or monomethyl fumarate (zinc salts). Therapeutic doses after an
initial phase may, for example, be comprised of 20 mg of dimethyl
fumarate, 87 mg of monoethyl fumarate (calcium salt) and 3.0 mg of
monoethyl fumarate or monomethyl fumarate (zinc salt).
For example, the fumaric acid derivatives used in the invention are
obtained according to the processes described in EP 0 312 697.
Without wishing to be bound by theoretic contemplations, it is
assumed that the gastro-intestinal symptoms may be caused by local
stimulation of the epithelial cells of the intestine which induces
TNF-.alpha. secretion. Upon administration of conventional tablets,
the ingredients of these tablets are released in the intestine in a
concentration which is too high, causing local irritation of the
intestinal mucous membrane. As a result of this local irritation
very high concentrations of TNF-.alpha. are presumably released for
a short period of time which may be responsible for the
gastrointestinal side effects. On the other hand, when
enteric-coated micro-tablets in capsules are applied, locally low
concentrations of the active ingredients on the epithelial cells of
the intestine are achieved. By peristaltic movements of the
stomach, the micro-tablets are gradually moved into the small
intestine with enhanced distribution of the active ingredients.
In other words, enteric-coated micro-tablets in the same dose
disperse in the stomach already and are fed to the intestine in
portions (boluswise), where the active ingredients are released in
smaller doses. As a result, local irritation of the epithelial
cells of the intestine and the release of TNF-.alpha. are avoided.
This is a possible explanation for the enhanced toleration of
micro-tablets in the gastro-intestinal tract vis-a-vis conventional
tablets. However, it was not to be expected that a mere change in
galenics would lead to such a drastic reduction of side
effects.
The following examples will show the production and action of the
micro-tablets according to the invention.
EXAMPLE 1
Preparation of Enteric-coated Micro-tablets in Capsules Containing
87.0 mg of Monoethyl Fumarate-Ca Salt, 120.0 mg of Dimethyl
Fumarate and 5.0 mg of Monoethyl Fumarate-Mg Salt, Which
Corresponds to a Total of 164 mg of Fumaric Acid
Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.), 8.700 kg of monoethyl fumarate-Ca salt,
12.000 kg of dimethyl fumarate, 0.500 kg of monoethyl fumarate-Mg
salt and 0.30 kg of monoethyl fumarate-Zn salt are crushed,
intensely mixed and homogenised by means of a sieve 800. Then an
excipient mixture of the following composition is prepared: 18.00
kg of starch derivative (STA-RX.RTM. 1500), 0.30 kg of
micro-crystalline cellulose (Avicel.RTM. PH 101), 0.75 kg of PVP
(Koilidon.RTM. 120), 4.00 kg of Primogel.RTM., 0.25 kg of colloidal
silicic acid (Aerosil.RTM.). The entire powder mixture is added to
an active ingredient mixture, homogenised by means of a sieve 200,
processed in the usual manner with a 2% aqueous solution of
polyvinyl pyrrolidone (Kollidon.RTM. K25) to obtain a binder
granulate and mixed in a dry state with the outer phase consisting
of 0.50 kg of Mg stearate and 1.50 kg of talcum. Then the powder
mixture is pressed by the conventional method into convex
micro-tablets with a gross mass of 10.0 mg and a diameter of 2.0
mm. Instead of this classic tabletting method other methods for
making tablets such as direct tabletting or a method for making
solid dispersions by the melt method and the spray drying method
may also be used.
The gastric acid-resistant coating may be poured or sprayed on in a
classic coating pan or applied in a fluidised-bed apparatus. In
order to achieve resistance to gastric acid, portions of a solution
of 2.250 kg of hydroxy propyl methyl cellulose phthalate (HPMCP,
Pharmacoat.RTM. HP 50) are dissolved in a mixture of the following
solvents: acetone 13.00 1, ethanol (94% by weight denatured with 2%
ketone) 13.50 1 and demineralised water 1.50 1. 0.240 kg of castor
oil are added as softening agent to the finished solution and
applied in portions to the tablet cores in the usual manner.
After drying is completed, a suspension of the following
composition is applied as a film-coat in the same apparatus: talcum
0.340 kg, titanium(VI) oxide Cronus RN 56 0.400 kg, coloured
lacquer L red lacquer 86837 0.324 kg, Eudragit E 12.5% 4.800 kg and
polyethylene glycol 6000 pH 11 XI 0.120 kg in a solvent mixture of
the following composition: 2-propanol 8.170 kg, aqua demineralisata
0.200 kg and glycerine triacetate (Triacetin) 0.600 kg.
The enteric-coated micro-tablets are then filled into hard gelatine
capsules at a net weight of 500.0 mg and sealed.
EXAMPLE 2
Preparation of enteric-coated Micro-tablets in Capsules Containing
87.0 mg of Monoethyl Fumarate-Ca Salt, 120.0 mg of Dimethyl
Fumarate and 5.0 mg of Monoethyl Fumarate-Mg Salt, which
Corresponds to a Total of 164 mg of Fumaric Acid
Taking the necessary precautions (breathing mask, gloves,
protective clothing, etc.), 8.700 kg of monoethyl fumarate-Ca salt,
12.000 kg of dimethyl fumarate, 0.500 kg of monoethyl fumarate-Mg
salt and 0.30 kg of monoethyl fumarate-Zn salt are crushed,
intensely mixed. and homogenised by means of a sieve 800. Then an
excipient mixture of the following composition is prepared: 24.70
kg of micro-crystalline cellulose (Avicel.RTM. PH 200), 3.00 kg of
croscarmellose sodium (AC-Di-SOL-SD-711), 2.50 kg of talcum, 0.10
kg of anhydrous silica (Aerosil.RTM. 200) and 1.00 kg of magnesium
stearate. The entire excipient mixture is added to the active
ingredient mixture and homogenised. Then the powder mixture is
pressed by direct tabletting into convex micro-tablets with a gross
mass of 10.0 mg and a diameter of 2.0 mm. Instead of this classic
tabletting method other methods for making tablets such as solid
dispersions by the melt method, the spray drying method or
tabletting of binder granulates may also be used.
The gastric acid-resistant coating may be poured or sprayed on in a
classic coating pan or applied in a fluidised-bed apparatus. For
example, a solution of 0,94 kg of Eudragita L in isopropanol is
prepared which also contains 0.07 kg of dibutyl phthalate. This
solution is sprayed onto the tablet cores.
After that, a dispersion of 17.32 kg of Eudragit.RTM. L D-55 and a
mixture of 2.80 kg of micro-talcum, 2.00 kg of Macrogol 6000 and
0.07 kg of Dimetican in water is prepared and sprayed onto the
cores.
The enteric-coared micro-tablets are then filled into hard gelatine
capsules at a net weight of 760.0 mg and sealed.
Therapy examples
Micro-tablets containing the same four active ingredients in the
same quantitative composition as the commercial product
Eumaderm.RTM. were prepared according to the above production
examples. A Fumaderm.RTM. tablet with enteric coating corresponds
to about 102 enteric-coated micro-tablets having the same
composition. As described in the production examples, these
micro-tablets are filled into capsules for more convenient
administration. Two capsules correspond to one tablet of
Fumadermo.
For easier comparison, two patients who developed severe
gastro-intestinal symptoms during therapy with Fumaderm.RTM.
tablets were treated with the enteric-coated micro-tablets
according to the invention. After administration of these
micro-tablets, these patients surprisingly no longer complained
about gastro-intestinal troubles which had been observed during
administration of conventional tablets. The same improvement of
psoriasis was observed as with Fumaderm.RTM. tablets of the prior
art. Under certain circumstances, a smaller dose may suffice to
achieve clinical success when micro-tablets are administered.
The results of the treatment are presented in the following
table:
Patient 1 Patient 2 Product* Initials M.M. W.F. Age 63 54 Sex
female male Dose Jan. 1 to 1985: 3 tablets Fumaderm .RTM. initial/
April 1, 1998 of Fumaderm/ Fumaderm .RTM. of Fumaderm day initial
GI symptoms cramps, pain pain in the Fumaderm .RTM. initial/
epigastric Fumaderm .RTM. region Severity of GI severe severe
Fumaderm .RTM. initial/ symptoms Fumaderm .RTM. Clinical evalu-
satisfactory satisfactory Fumaderm .RTM. initial/ ation of Fumaderm
.RTM. psoriasis Interruption of none 1985- Fumaderm .RTM. initial/
therapy May 12, 1998 Fumaderm .RTM. Dose Apr. 1-6, 1998 May 13-
Fumaderm .RTM. P mikro 3 capsules/day 20, 1998 Apr. 7- 3
capsules/day May 10, 1998 May 21- 9 capsules/day July 1, 1998 May
11- 6 capsules/day Aug. 31, 1998 3 capsules/day GI symptoms none
May 15- " 18, 1998 winds Severity of -- slight " symptoms Clinical
evalu- very good good " ation of psoriasis *1 Fumaderm .RTM. tablet
corresponds to two capsules of Fumaderm P mikro GI =
gastrointestinal
The table shows that even an increased dose of micro-tablets (9
capsules per day) had no or only slight side effects, while the
lower dose of the commercial product Fumaderm.RTM. already caused
severe gastro-intestinal symptoms.
The results of the treatment also show that the effectiveness of
micro-tablets for treating psoriasis is at least equivalent, if not
better than that of the commercial product. On the whole, the
formulation of fumaric acid derivates in the form of micro-tablets
therefore show a significant improvement vis-a-vis therapy with
conventional tablets.
* * * * *